Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide
ABSTRACT The inhibitory effect of Andrographis paniculata extract (APE) and andrographolide (AND), the most medicinally active phytochemical in the extract, on hepatic cytochrome P450s (CYPs) activities was examined using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-O-deethylation, CYP2B1-dependent benzyloxyresorufin-O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation and CYP3A-dependent testosterone 6 beta-hydroxylation activities, were determined in the presence and absence of APE or AND (0-200 microM). APE inhibited ethoxyresorufin-O-deethylation activity in rat and human liver microsomes, with apparent Ki values of 8.85 and 24.46 microM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent Ki values of 8.21 and 7.51 microM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with Ki of 25.43 microM. AND was found to be a weak inhibitor of rat CYP2E1 with a Ki of 61.1 microM but did not affect human CYP2E1. In conclusion, it cannot be excluded from the present study that APE could cause drug-drug interactions in humans through CYP3A and 2C9 inhibition.
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- "Preparation of aqueous SC extract SC powder was mixed 1:3 with water (w/v) using a Soxhlet apparatus for 3 h. The mixture was filtered and the filtrate was dried under reduced pressure using a rotary evaporator at low temperature(0–4 1C) as described previously (Pekthong et al., 2008). The contents of the four lignans in the prepared aqueous extract of SC, determined according to an established HPLC–MS method (Wang et al., 2008), included 0.04% (w/v) schisantherin A and 0.029% (w/v) deoxyshisandrin with undetectable schisandrin and γ-schisandrin. "
ABSTRACT: Ethnopharmacological relevance: Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. Material and methods: Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat. Results: SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5 g/kg, qd x 7d) and alcoholic extract (1.5 g/kg, qd x 7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and gamma-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated C-max (10 fold). Conclusion: These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.Journal of Ethnopharmacology 08/2014; 155(3). DOI:10.1016/j.jep.2014.07.026 · 2.94 Impact Factor
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- "The antimalarial properties of a tropical plant Andrographis paniculata has been studied in details recently by Mishra et al. , and also, there are several reports that demonstrate the antimalarial properties of the plant A. paniculata [4– 6], but there is hardly any report that describe the active compound responsible for the anti-malarial property of this plant. Andrographolide, the diterpenic lactone compound, is one of the major phytoconstituents of the plant A. paniculata and has been reported to have diverse pharmacological potential including antiviral , anti-inflammatory    , and anticancer properties . The present study for the first time establishes andrographolide as the major bioactive anti-malarial constituent of the plant A. paniculata using both in vitro and in vivo approaches. "
ABSTRACT: Andrographolide (AND), the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plant Andrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages of Plasmodium falciparum in vitro and Plasmodium berghei ANKA in vivo. IC50s for artesunate (AS), andrographolide (AND), and curcumin (CUR) were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND) was found synergistic with curcumin (CUR) and addictively interactive with artesunate (AS). In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%), compared to the control (81%), but also by extending the life span by 2-3 folds. Being nontoxic to the in vivo system this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.Journal of Tropical Medicine 06/2011; 2011:579518. DOI:10.1155/2011/579518
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ABSTRACT: Andrographis paniculata (Burm.f) Nees is one of the most popular and important medicinal plant of the Orient, and South East Asia. It finds mention in various forms in Indian, Chinese, Malay, Thai, Unani, and Japanese systems of medicine. The plant exhibits anti-cancer, anti-inflammatory, anti-diabetic, anti-hypertensive, anti-venom, cholestatic, hepatoprotective, anti-thrombotic, anti-retroviral, anti-microbial, anti-pyretic, anti-malarial, anti-oxidant, immunomodulatory, and cardioprotective effects. The major active principles contributing to biological activity are diterpene lactones, but flavonoids, xanthones and caffeic acid derivatives also contribute to anti-oxidant, anti-proliferative, anti-atherosclerotic, and anti-malarial effects. As a result of its wide spectrum of pharmacological activity, almost impeccable safety profile, being a widely cultivated medicinal plant, we have collected and compiled various facets of this plant. Extensive datamining of the phytochemistry and pharmacology of Andrographis paniculata revealed more than 50 diterpene lactones, 30 flavonoids, 8 quinic acid derivatives, and 4 xanthones. This review contains information on around 80 isolated compounds, out of which more than half of the compounds have no reported pharmacological activity. Though there are some good reviews available on Andrographis paniculata, the authors of the earlier reviews focused on one or two aspects of the plant and none have attempted to integrate the available information on this plant. This provided us the much needed impetus, warranting a full-fledged and complete review on Andrographis paniculata, one of the most popular and important Oriental medicinal plant.Phytochemistry Reviews 03/2011; 11(1). DOI:10.1007/s11101-011-9219-z · 2.89 Impact Factor